This invention relates generally to novel substituted aryl hydroxamic acid derivatives as metalloproteinase inhibitors, and inhibitors of TNF, pharmaceutical compositions containing the same, and methods of using the same.
There is now a body of evidence that metalloproteinases (MP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. In addition metalloproteinases have been shown to be involved in the processing of cell surface proteins that have been implicated in a number of diseases, including inflammatory disorders.
Tumor necrosis factor alpha (TNF-xcex1) is a cell associated cytokine that is processed from a 26 kd precursor form to a 17 kd active form. TNF-xcex1 has been shown to be a primary mediator in humans and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock. Excess TNF-xcex1 has been shown to be lethal. There is now considerable evidence that blocking the effects of TNF-xcex1 with specific antibodies can be beneficial in a variety of circumstances including autoimmune diseases such as rheumatoid arthritis (Feldman et al, Lancet, 1994, 344, 1105) and non-insulin dependent diabetes melitus. (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22) and Crohn""s disease (MacDonald T. et al. Clin. Exp. Immunol. 81, 1990, 301).
Compounds which inhibit the production of TNF-xcex1 are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently it has been shown that a matrix metalloproteinase (MMP) or family of metalloproteinases, hereafter known as TNF-convertases (TNF-C), as well as other MP""s are capable of cleaving TNF-xcex1 from its cell associated to soluble form (Gearing et al Nature, 1994, 370, 555). This invention describes molecules that inhibit this conversion and hence the secretion of active TNF-xcex1 from cells.
The compounds of the current invention inhibit the production of TNF-xcex1 from cells stimulated with LPS. Furthermore, some of the present compounds are selective for TNF-C inhibition over matrix metalloproteinases. This selectivity offers a distinct advancement over compounds of the current art, because non-selective MMP inhibitors have been found to produce toxic manifestations related to tendonitis and fibroplasia in clinical trials.
The compounds of the current invention do not inhibit MMPs at concentrations expected to produce a therapeutically positive response through the inhibition of TNF. The compounds of the present invention are therefore expected to be safer to patients taking the drug because of their selective inhibition profile for soluble TNF-xcex1 production.
The present novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restricted to septic shock, haemodynamic shock, sepsis syndrom, post ischaemic reperfusion injury, malaria, Crohn""s disease, inflammatory bowel diseases, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancer, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, osteo and rheumatoid arthritis, multiple sclerosis, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV, neuro-denerative diseases and non-insulin dependent diabetes melitus.
Since excessive TNF-xcex1 production has been noted in several disease conditions also characterized by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF-xcex1 production may also have a particular advantage in diseases where both mechansisms are involved.
WO 97/20824 describes MMP inhibitors of formula A: 
wherein ring V contains six atoms, Z is O or S, and Ar is an aryl or heteroaryl group. Ar is preferably a monocyclic aryl group with an optional para substituent or an unsubstituted monocyclic heteroaryl group. WO 97/20824 does not disclose any compounds wherein Ar is a disubstituted phenyl or pyridyl or a bicyclic heteroaryl group.
The compounds of the current invention act as inhibitors of MPs, that process TNF-xcex1. These novel molecules are provided as anti-inflammatory compounds and cartilage protecting therapeutics. The inhibiton of TNF-C, and other metalloproteinases by molecules of the present invention indicates they are anti-inflammatory.
Accordingly, one object of the present invention is to provide novel substituted aryl hydroxamic acids which are useful as metalloprotease inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating inflammatory disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, p, X, Y, Z, Rb, R1, R2, R3, and R4 are defined below, are effective metalloprotease inhibitors with unique and specific inhibitory properties for TNF.
[1] Thus, in a first embodiment, the present invention provides a novel compound of formula I: 
xe2x80x83or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
ring A is a 5-8 membered heterocyclic ring containing 0-1 additional heteroatoms selected from the group: O, NH, S, SO, and SO2, and substituted with 0-3 Ra;
Ra, at each occurrence, is independently selected from the group: xe2x95x90O, CH3, CH2CH3, CF3, Cl, F, OH, OCH3, and OCF3;
Rb, at each occurrence, is independently F or CH3;
X is selected from the group: CH2, C(O), C(O)O, C(O)NH, S(O), S(O)2, S(O)NH, and S(O)2NH;
Y is selected from the group: (CH2)n, OCH2, CH2O, OCH(CH3), CH(CH3)O, OC(CH3)2, C(CH3)2O, OCF2, CF2O, S(O)pCH2, CH2S(O)p, NH, NHCH2, and CH2NH;
Z is CH or N;
R1 is selected from the group: H, F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CF3, and OCF3;
R2 is selected from the group: F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CF3, and OCF3;
R3 is selected from the group: F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CF3, and OCF3;
provided that when Z is N, R2 and R3 are other than F, Br, or I;
R4 is H;
alternatively, R3 and R4 are taken together with the carbon atoms to which they are attached to form a 5-6 membered aromatic ring containing 0-2 heteroatoms selected from the group: O, S, NH, and N and substituted with 0-2 Rc;
Rc is selected from the group: H, F, Cl, Br, I, NO2, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CF3, and OCF3;
when R3 and R4 are taken together, then R2 is selected from the group: H, F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CF3, and OCF3;
n is selected from the group: 1, 2, and 3; and,
p is selected from the group: 0, 1, and 2.
[2] In a preferred embodiment, the present invention provides a compound of formula Ia or Ib: 
xe2x80x83wherein,
X is selected from the group: CH2, C(O), C(O)O, C(O)NH, S(O), S(O)2, S(O)NH, and S(O)2NH;
Y is selected from the group: CH2, (CH2)2, OCH2, CH2O, NH, NHCH2, and CH2NH;
Z is CH or N;
R1 is selected from the group: H, F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CF3, and OCF3;
R2 is selected from the group: F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CF3, and OCF3;
R3 is selected from the group: F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CF3, and OCF3;
R4 is H;
alternatively, R3 and R4 are taken together with the aromatic ring to which they are attached to form an aromatic ring selected from a-aa: 
Rc is selected from the group: H, F, Cl, Br, I, NO2, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CF3, and OCF3; and,
R2a is selected from the group: H, F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CF3, and OCF3.
[3] In an even further preferred embodiment, the present invention provides novel compounds selected from:
(S)-4-[[4-[(3,5-dimethylphenyl)methoxy]phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-3-thiomorpholinecarboxamide;
(S)-4-[[4-[(3,5-dimethoxyphenyl)methoxy]phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-3-thiomorpholinecarboxamide;
(S)-4-[[4-[(3,5-ditrifluoromethylphenyl)methoxy]phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-3-thiomorpholinecarboxamide;
(S)-4-[[4-[(3,5-dibromophenyl)methoxy]phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-3-thiomorpholinecarboxamide;
(S)-4-[[4-[(3,5-diethoxyphenyl)methoxy]phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-3-thiomorpholinecarboxamide;
(S)-4-[[4-[(3,5-dichlorophenyl)methoxy]phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-3-thiomorpholinecarboxamide;
(S)-4-[[4-[(2,6-dimethyl-4-pyridinyl)methoxy]phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-3-thiomorpholinecarboxamide;
(S)-4-[[4-[(2,6-dimethoxy-4-pyridinyl)methoxy]phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-3-thiomorpholinecarboxamide;
(S)-4-[[4-[(2,6-diethoxy-4-pyridinyl)methoxy]phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-3-thiomorpholinecarboxamide;
(S)-4-[[4-[(2,6-ditrifluoromethyl-4-pyridinyl)methoxy]phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-3-thiomorpholinecarboxamide;
(S)-4-[[4-[(2,6-dichlorol-4-pyridinyl)methoxy]phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-3-thiomorpholinecarboxamide;
(S)-N-hydroxy-2,2-dimethyl-4-[[4-(4-quinolinylmethoxy)phenyl]sulfonyl]-3-thiomorpholinecarboxamide;
(S)-N-hydroxy-2,2-dimethyl-4-[[[4-(2-methyl-4-quinolinyl)methoxy]phenyl]sulfonyl]-3-thiomorpholinecarboxamide;
(S)-N-hydroxy-2,2-dimethyl-4-[[[4-(2-chloro-4-quinolinyl)methoxy]phenyl]sulfonyl]-3-thiomorpholinecarboxamide;
(S)-N-hydroxy-2,2-dimethyl-4-[[[4-(2-methoxy-4-quinolinyl)methoxy]phenyl]sulfonyl]-3-thiomorpholinecarboxamide;
(S)-N-hydroxy-2,2-dimethyl-4-[[[4-(2-ethoxy-4-quinolinyl)methoxy]phenyl]sulfonyl]-3-thiomorpholinecarboxamide;
(S)-N-hydroxy-2,2-dimethyl-4-[[[4-(2-trifluoromethyl-4-quinolinyl)methoxy]phenyl]sulfonyl]-3-thiomorpholinecarboxamide;
1-[[4-[(3,5-dimethylphenyl)methoxy]phenyl]sulfonyl]-D-proline-N-hydroxyamide;
1-[[4-[(3,5-dimethoxyphenyl)methoxy]phenyl]sulfonyl]-D-proline-N-hydroxyamide;
1-[[4-[(3,5-ditrifluoromethylphenyl)methoxy]phenyl]sulfonyl]-D-proline-N-hydroxyamide;
1-[[4-[(3,5-dibromophenyl)methoxy]phenyl]sulfonyl]-D-proline-N-hydroxyamide;
1-[[4-[(3,5-diethoxyphenyl)methoxy]phenyl]sulfonyl]-D-proline-N-hydroxyamide;
1-[[4-[(3,5-dichlorophenyl)methoxy]phenyl]sulfonyl]-D-proline-N-hydroxyamide;
1-[[4-[(2,6-dimethyl-4-pyridinyl)methoxy]phenyl]sulfonyl]-D-proline-N-hydroxyamide;
1-[[4-[(2,6-dimethoxy-4-pyridinyl)methoxy]phenyl]sulfonyl]-D-proline-N-hydroxyamide;
1-[[4-[(2,6-diethoxy-4-pyridinyl)methoxy]phenyl]sulfonyl]-D-proline-N-hydroxyamide;
1-[[4-[(2,6-ditrifluoromethyl-4-pyridinyl)methoxy]phenyl]sulfonyl]-D-proline-N-hydroxyamide;
1-[[4-[(2,6-dichloro-4-pyridinyl)methoxy]phenyl]sulfonyl]-D-proline-N-hydroxyamide;
1-[[4-(4-quinolinylmethoxy)phenyl]sulfonyl]-D-proline-N-hydroxyamide;
1-[[[4-(2-chloro-4-quinolinyl)methoxy]phenyl]sulfonyl]-D-proline-N-hydroxyamide;
1-[[[4-(2-methyl-4-quinolinyl)methoxy]phenyl]sulfonyl]-D-proline-N-hydroxyamide;
1-[[[4-(2-methoxy-4-quinolinyl)methoxy]phenyl]sulfonyl]-D-proline-N-hydroxyamide;
1-[[4-(2-ethoxy-4-quinolinyl)methoxy]phenyl]sulfonyl]-D-proline-N-hydroxyamide;
1-[[[4-(2-trifluoromethyl-4-quinolinyl)methoxy]phenyl]sulfonyl]-D-proline-N-hydroxyamide;
(S)-N-hydroxy-2,2-dimethyl-4-[[[4-(3-methyl-4-quinolinyl)methoxy]phenyl]sulfonyl]-3-thiomorpholinecarboxamide;
(S)-N-hydroxy-2,2-dimethyl-4-[[[4-(3-chloro-4-quinolinyl)methoxy]phenyl]sulfonyl]-3-thiomorpholinecarboxamide;
(S)-N-hydroxy-2,2-dimethyl-4-[[[4-(3-methoxy-4-quinolinyl)methoxy]phenyl]sulfonyl]-3-thiomorpholinecarboxamide;
1-[[[4-(3-chloro-4-quinolinyl)methoxy]phenyl]sulfonyl]-D-proline-N-hydroxyamide;
1-[[[4-(3-methyl-4-quinolinyl)methoxy]phenyl]sulfonyl]-D-proline-N-hydroxyamide; and,
1-[[[4-(3-methoxy-4-quinolinyl)methoxy]phenyl]sulfonyl]-D-proline-N-hydroxyamide;
or a pharmaceutically acceptable salt form thereof.
[4] In a second embodiment, the present invention provides a novel compound of formula II: 
xe2x80x83or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
ring A is a 5-8 membered heterocyclic ring containing 0-1 additional heteroatoms selected from the group: O, NH, S, SO, and SO2, and substituted with 0-3 Ra;
Ra, at each occurrence, is independently selected from the group: xe2x95x90O, CH3, CH2CH3, CF3, Cl, F, OH, OCH3, and OCF3;
Rb, at each occurrence, is independently F or CH3;
X is selected from the group: CH2, C(O), C(O)O, C(O)NH, S(O), S(O)2, S(O)NH, and S(O)2NH;
Yxe2x80x2 is S or O;
Z is CH or N;
R1 is selected from the group: H, F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CF3, and OCF3;
R2 is selected from the group: F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CF3, and OCF3;
R3 is selected from the group: H, F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CF3, and OCF3;
provided that when Z is N, R2 and R3 are other than F, Br, or I;
R4 is H;
alternatively, R3 and R4 are taken together with the carbon atoms to which they are attached to form a 5-6 membered aromatic ring containing 0-2 heteroatoms selected from the group: O, S, NH, and N and substituted with 0-1 Rc;
Rc is selected from the group: H, F, Cl, Br, I, NO2, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CF3, and OCF3;
when R3 and R4 are taken together, then R2 is selected from the group: H, F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CF3, and OCF3;
n is selected from 1, 2, and 3; and,
p is selected from 0, 1, and 2.
[5] In a preferred embodiment, the present invention provides a compound of formula IIa, IIb, IIc or IId: 
xe2x80x83wherein, X is selected from the group: CH2, C(O), C(O)O, C(O)NH, S(O), S(O)2, S(O)NH, and S(O)2NH;
Z is CH or N;
R1 is H or F;
R2 is selected from the group: F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CF3, and OCF3;
R3 is selected from the group: F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CF3, and OCF3;
R4 is H;
alternatively, R3 and R4 are taken together with the aromatic ring to which they are attached to form an aromatic ring selected from a-aa: 
Rc is selected from the group: H, F, Cl, Br, I, NO2, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CF3, and OCF3; and,
R2a is selected from the group: H, F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CF3, and OCF3.
In a third embodiment, the present invention provides a novel pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt form thereof.
In a fourth embodiment, the present invention provides a novel method for treating or preventing an inflammatory disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt form thereof.
In a fifth embodiment, the present invention provides a novel method of treating a condition or disease mediated by MMPS, TNF, aggrecanase, or a combination thereof in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt form thereof.
In a sixth embodiment, the present invention provides a novel method of reducing levels of TNF in patients without inhibiting MMPs, comprising: MMP-1, MMP-2, and MMP-9, and reduce the potential of side effects mediated by these enzymes comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt form thereof.
In a seventh embodiment, the present invention provides a novel method of treating a condition or disease wherein the disease or condition is referred to as rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, multiple sclerosis, neurodegenerative diseases, psoriasis, autoimmune disease, Crohn""s disease, inflammatory bowel disease, or HIV infection in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt form thereof.
In a eighth embodiment, the present invention provides a novel method of treating a condition or disease wherein the disease or condition is referred to as fever, cardiovascular effects, hemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, shock, graft versus host reaction, solid tumor growth and tumor invasion by secondary metastases, or neovascular glaucoma, in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt form thereof.
An ninth embodiment of the invention provides novel preferred compounds that are orally bioavailable and selective for the inhibition of TNF-xcex1 through its convertase(s), over enzymes of the matrix metalloproteinase class.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
The present invention includes all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
When any variable (e.g., Rb) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9cC1-6 alkylxe2x80x9d or xe2x80x9cC1-6 alkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl; xe2x80x9cAlkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. xe2x80x9cAlkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, and the like.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 5- to 8-membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H, 6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively.
Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work up procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
A series of 4-substituted aryl sulfonamides of formula 7 are described in Scheme 1. A suitable cyclic amino ester scaffold (1) was treated with 4-hydroxybenzenesulfonyl chloride (2, R. W. Campbell, H. W. Hill, Jr. J. Org. Chem., 1975, 38, 1047) to provide hydroxy aryl sulfonamide 3. Coupling of 3 to 4 can be accomplished by Mitsunobu reaction (DEAD, TEA, R5xe2x95x90OH) or by formation of the alkaline salt of 3, by treatment with an alkaline carbonate in a polar aprotic solvent, then reaction with 4 (R5xe2x95x90Cl, Br, I, OSO2CH3, OSO2Ar) to give biaryl sulfonamide 5. Saponification of the ester could be accomplished by acidic (6N HCl reflux) or basic conditions (LiOH, THF:H2O) to afford carboxylic acid 6 which could be converted to the hydroxamic acid under a variety of conditions with the preferred being BOP reagent, DIEA, and hydroxylamine hydrochloride. 
Another synthetic sequence for the synthesis of 7 constructs the biarylsulfonamide portion and then couples it to scaffold 1 (Scheme 2). Starting with phenol 8, 4 was attached using the same Mitsunobu or alkylation conditions previously described in Scheme 1 to provide the alkylated phenol 9. In this scheme, 4 was chosen with the proviso that it must allow regioselective chlorosulfonylation on the phenol ring of 9 in sufficient yield to continue the synthetic sequence. Useful conditions for conversion of 9 to 10 are chlorosulfonic acid in an appropriate solvent at an appropriate temperature. An alternative synthesis was to begin the sequence with 4-bromophenol then append the chlorosulfonyl group on by a metallation, sulfuryl chloride quench sequence. Reaction of scaffold 1 with sulfonyl chloride 10 then gave intermediate 5 which can be converted to 7 by the conditions previously discussed in Scheme 1. 
Synthesis of 16 with an aminomethyl attachment between the aryl groups in the sulfonamide side chain can be accomplished by the sequence outlined in Scheme 3. Scaffold 1 was reacted with 4-nitrobenzesulfonyl chloride to provide 12. The nitro group was then reduced to afford amine 14. Substitution of the nitrogen can be accomplished by treatment of 13 with aldehyde 14 under reductive alkylation conditions (sodium cyanoborohydride, methanol being typical) to give biaryl sulfonamide 15. The ester 15 was then converted to the hydroxamate 16 by standard conditions. 
Synthesis of hydroxamate 21 where the connection between the benzenesulfonamide and the other aromatic group is CH2NH, CH2O, or CH2S is outlined in Scheme 4. Scaffold 1 was reacted with 4-bromomethylbenzensulfonyl chloride to give aryl sulfonamide 18. Displacement of the bromide could be accomplished with aryl or heteroaryl amines, alcohols or thiols to provide 20. The ester 20 was then converted to the hydroxamate 21 under the conditions previously discussed. 
The biaryl ether and biaryl amine analogs 23 and 25 can be prepared from 4-hydroxybenzensulfonamide 3 according the procedures outlined in Scheme 5. The biaryl ether analogs are prepared directly from 3 by treatment with an aryl boronic acid in the presence of cupric acetate and amine base (Chan, D. M. T.; Winters, M. P.; Monaco, K. L.; Wang, R. 35th Nat. Organic Symposium, San Antonio, Tex., Jun. 24, 1997, Abstract M92) to give 22 which was then converted to hydroxamate 23. Biaryl amines are synthesized from 3 by first synthesis of triflate 24 (Tf2O, TEA) then coupling with aryl amines 25 (Louie, J.; Driver, M. S.; Hamann, B. C.; Hartig, J. F. J. Org. Chem. 1997, 62(5), 1268-73, Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1997, 62(5), 1264-67) provide biarylaminesulfonamide 25 which is converted to the hydroxamate 26 under the usual conditions. 
An example of the synthesis of a preferred 3-thiomorpholine scaffold is given in Scheme 6. Thiomorpholine 29 was reacted with 4-hydroxybenzensulfonyl chloride in pyridine to give hydroxysulfonamide 30. Alkylation with cesium carbonate and 4-chloromethyl-2,6-dimethylpyridine hydrochloride afforded ether sulfonamide 31 in good yield. Saponification was accomplished with 6N HCl under reflux for 15 h then treatment with BOP reagent, DIEA, and hydroxylamine hydrochloride provided the hydroxamate 33. 
One diastereomer of a compound of Formula I may display superior activity compared with the others. When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy, 1995, 2602-2605. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Andrew S. Thompson, et al, Tet. lett. 1995, 36, 8937-8940).
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.